Parametric studies of antipsychotic-induced sensitization in the conditioned avoidance response model: roles of number of drug exposure, drug dose, and test-retest interval

Abstract

Repeated haloperidol and olanzapine treatment produces an enhanced disruption of avoidance responding, a validated measure of antipsychotic activity. Experimental parameters affecting this sensitization-like effect have not been thoroughly examined. The present study investigated the role of three parameters (number of injections, dose, and interval between initial exposure and challenge) in antipsychotic sensitization in the conditioned avoidance response paradigm. Well-trained Sprague-Dawley rats received different numbers of drug treatment (1-5 days) or different doses of haloperidol (0.025-0.10 mg/kg, subcutaneously) or olanzapine (0.5-2.0 mg/kg, subcutaneously). After certain time intervals (4, 10 or 17 days), they were tested for the expression of haloperidol or olanzapine sensitization in a challenge test in which all rats were injected with a lower dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg). Throughout the drug-treatment period, both haloperidol and olanzapine dose-dependently enhanced their disruption of avoidance responding. Three days later, the sensitization induced by a low dose of haloperidol (0.025 mg/kg) or olanzapine (0.5 mg/kg) was only apparent in rats that received treatment for 5 days, but not in those that received treatment for 1-4 days. The sensitization induced by the medium and high doses of haloperidol (0.05 and 0.10 mg/kg) or olanzapine (1.0 and 2.0 mg/kg) was still robust even with only 3 days of treatment. The sensitization induced by a 3-day haloperidol (0.10 mg/kg) and olanzapine (2.0 mg/kg) treatment was long-lasting, still detectable 17 days after the last drug treatment. This study suggests that antipsychotic sensitization is a robust behavioral phenomenon. Its induction and expression are strongly influenced by parameters such as number of drug exposures, drug dose, and test-retest interval. Given the importance of antipsychotic sensitization in the maintenance of antipsychotic effects in the clinic, this study introduces a paradigm that can be used to investigate the behavioral and neurobiological mechanisms underlying antipsychotic sensitization.

Fig. 1

A schematic representation of the experimental procedure in experiments 1 and 2. HAL, haloperidol; OLZ, olanzapine; VEH, vehicle.

Fig. 2

A schematic representation of the experimental procedure in experiments 3 and 4. HAL, haloperidol; OLZ, olanzapine.

Fig. 3

A schematic representation of the experimental procedure in experiments 5 and 6.

Fig. 4

(a) Effect of repeated haloperidol (HAL) treatment (0.025 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats in the final training day (drug-free), 50 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM. Different groups of rats received either 0, 1, 2, 3, 4, or 5 days of HAL (*P<0.05). (b) Effect of number of drug exposure days on final challenge day. All groups were injected with HAL (0.025 mg/kg) and avoidance responses were measured (*P<0.05). VEH, vehicle.

Fig. 5

(a) Effect of repeated olanzapine (OLZ) treatment (0.5 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats in the final training day (drug-free), 5 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM. Different groups of rats received either 0, 1, 2, 3, 4, or 5 days of olanzapine (*P<0.05). (b) Effect of number of drug exposure days on final challenge day. All groups were injected with OLZ (0.5 mg/kg) and avoidance responses were measured (*P<0.05). VEH, vehicle.

Fig. 6

(a) Effect of repeated haloperidol (HAL) treatment (0.025, 0.05, or 0.1 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats on the final training day (drug-free), 3 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM (*P<0.05). (b) Effect of dose on final challenge day. All groups were injected with HAL (0.025 mg/kg) and avoidance responses were measured (*P<0.05). (c) Effect of dose on 10-trial blocks on challenge day. VEH, vehicle.

Fig. 7

(a) Effect of repeated olanzapine (OLZ) treatment (0.5, 1.0, or 2.0 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats on the final training day (drug-free), 3 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM (*P<0.05). (b) Effect of dose on final challenge day. All groups were injected with OLZ (0.5 mg/kg) and avoidance responses were measured (*P<0.05). VEH, vehicle.

Fig. 8

(a) Effect of repeated haloperidol (HAL) treatment (0.1 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats on the final training day (drug-free), 3 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM. Rats received either 1, 7, or 14 days of rest according to their group and were then retested in the conditioned avoidance response boxes (*P<0.05). (b) Effect of test–retest interval on final challenge day. All groups were injected with HAL (0.025 mg/kg) and avoidance responses were measured (*P<0.05). (c) Effect of dose on 10-trial blocks on challenge day. VEH, vehicle.

Fig. 9

(a) Effect of repeated olanzapine (OLZ) treatment (2.0 mg/kg, subcutaneously, 60 min) on conditioned avoidance responding across sessions. Number of avoidance responses made by the rats in the final training day (drug-free), 3 days of drug exposure, and two drug-free retesting sessions are expressed as mean±SEM. Rats received either 1, 7, or 14 days of rest according to their group and were then retested in the conditioned avoidance response boxes (*P<0.05). (b) Effect of test–retest interval on final challenge day. All groups were injected with OLZ (0.5 mg/kg) and avoidance responses were measured (*P<0.05).